Cancer & Sickle Cell Disease Treatments Can Increase Risk of Infertility

A group of international investigators have found that prepubertal boys treated with alkylating agent therapies or with hydroxyurea for sickle cell disease experience a significant reduction in their spermatogonial quantity, suggesting that some of these agents can affect fertility.

Before puberty, boys are not able to produce sperm samples that can be frozen and preserved for when they are older and might want to start their own family; however, transplanting testicular tissue back into patients after treatment is a potential way to restore fertility. Finding ways to generate sperm from preserved immature testicular tissue has been largely experimental though, and no pregnancies have resulted thus far. However, as a result of their findings, investigators suggest that if doctors plan to remove and freeze testicular tissue for fertility preservation, they should do this before boys undergo chemotherapy with alkylating agents.

For their study, led by Jan-Bernd Stukenborg, PhD, associate professor at the Karolinska Institute and University Hospital, in Stockholm, Sweden, the team examined histological sections of prepubertal testicular tissue to clarify whether chemotherapy exposure or primary diagnosis affects spermatogonial quantity.

To do this, the team assessed paraffin embedded testicular tissue samples collected for fertility preservation between 2014 and 2017 from 32 consecutive boy patients (aged 6.3 ± 3.8 [mean ± SD] years) living in Sweden, Finland, and Iceland, who were going to be starting treatments associated with high-risk of infertility. Treatments included testicular irradiation and chemotherapy or radiotherapy previous to a bone marrow transplant since they had cancer or a blood disorder, such as sickle cell disease. They also assessed quantity of spermatogonia per transverse tubular cross-section (S/T) in 14 control samples (from boys aged 5.6 ± 5.0 [mean ± SD] years) from a biobank at Karolinska hospital. Individuals with testicular volumes >10 ml. High bleeding and infection risk were excluded from the study.

Although 20 patients received the testicular biopsy 1 to 45 days after chemotherapy, 12 patients had not received any chemotherapy. Additionally, 14 testicular tissue samples of patients with no reported testicular pathology were included as control samples in addition to reference values obtained from a recently published meta-analysis. The investigators used morphological and immunohistochemical to assess the quantity of spermatogonia.

In their findings, the team found a significant reduction in spermatogonial cell counts in boys treated with alkylating agents or with hydroxyurea for sickle cell disease. In boys exposed to alkylating agents or in boys with sickle cell disease and exposed to hydroxyurea, the mean S/T values were significantly lower (P = 0.003 and P = 0.008, respectively) than those in a group exposed to non-alkylating agents or in biobank control samples (1.7 ± 1.0, n = 8 and 4.1 ± 4.6, n = 14, respectively). The mean S/T values of the testicular tissue samples included in the biobank control group, and the patient group exposed to non-alkylating agents were within recently published normative reference values, according to the study authors.

“The findings obtained in the current study should be used to inform health care professionals, patients, and their relatives about the increased risk of infertility for sickle cell disease patients treated with hydroxyurea,” Dr Stukenborg told Rare Disease Report^®. “Today, strategies to preserve fertility in boys unable to produce [their] own sperm are still highly experimental and no such experimental system has been proven to generate functional sperm for these boys.”

Therefore, he stressed the results presented in this study should be used to inform the public about the risk of becoming infertile. “Further research needs to be done to elucidate the reasons behind the decreasing germ cell counts in boys with sickle cell disease,” he added.

Echoing Dr Stukenborg’s call for additional research, the team also noted limitations and reasons for caution regarding the study. While testicular tissue samples from the internal biobank of Karolinska University Hospital considered to be normal (if no testicular pathology was reported in the analyzed sample) were included in the study, detailed information regarding previous medical treatments and testicular volumes of patients included in this biobank were not available.

Testicular tissue should be obtained before initiation of chemotherapy with alkylating agents for prepubertal boys in whom fertility preservation is indicated; however, according to the authors, this may not be possible for sickle cell disease patients, as cytotoxic exposure may not have been previously avoidable. The major group indicated to benefit from novel fertility preservation techniques is boys facing cancer and cytotoxic therapies.

“The next steps regarding the results obtained for the boys with sickle cell disease would be to find out if this decrease in germ cell numbers is directly related to the disease itself or the treatment with hydroxyurea,” added Dr Stukenborg. “To answer this question, more research needs to be done. Therefore, we are planning together with different pediatric hematology units as well as researchers working with fertility preservation across Europe future research projects focusing on this issue.”